Stress elicits adaptive responses from the brain, but it can also lead to maladaptive consequences. For example, stress can precipitate mental illness, including depression. Prolonged stress also causes damage to neurons in the hippocampus. Antidepressant drugs must be evaluated, not only for their ability to potentiate adaptive responses, but also to inhibit maladaptive consequences of stress. Ongoing research in our laboratory has compared the atypical tricyclic antidepressant, tianeptine, with the typical tricyclics, desipramine and imipramine, with respect to the effects of isolation and repeated restraint stress. Tianeptine and desipramine similarly attenuated isolation stress-induced increases in locus coeruleus and midbrain tyrosine hydroxylase mRNA levels and isolation-stress induced decreases in preproenkephalin mRNA levels in striatum and nucleus accumbens. However, tianeptine and imipramine differed in their effects in the cerebral cortex and hippocampus on 5HT2, and 5HT1A receptor levels but, surprisingly, produced similar effects on levels of the serotonin transporter labelled with [3H] paroxetine. Tianeptine also prevented stress-induced reductions in the length and number of branchpoints of dendrites of CA3 pyramidal neurons in hippocampus; comparison with effects of typical tricyclics are ongoing. Tianeptine also blocked effects of corticosterone treatment to reduce branching and length of CA3 dendrites. These actions of tianeptine may be due to interactions between 5HT and excitatory amino acids in the mossy fiber terminals on CA3 pyramidal neurons. Taken together, these results indicate that tianeptine has unique properties compared to some other antidepressant drugs, but shares in common with those drugs the ability to attenuate stress effects on tyrosine hydroxylase gene expression and on the serotonin transporter. It remains to be seen whether these actions are the basis of a common antidepressant action.

The role of α2-adrenergic autoreceptor desensitization in the delayed onset of antidepressant efficacy of selective norepinephrine (NE) reuptake inhibitors is unclear. Using the α2-antagonist yohimbine, we showed previously that chronic treatment with desipramine (DMI) did not alter autoreceptor-mediated inhibition of NE release in the cortex. However, yohimbine may have non-selective effects that could confound this interpretation. Thus, using microdialysis, we measured acute effects of the highly selective α2-antagonist atipamezole on NE release in the prefrontal cortex following chronic DMI treatment, after 0–8 d washout. Atipamezole induced a similar elevation of extracellular NE in all treatment groups, indicating no change in autoreceptor function. Further, the effect was most rapid in DMI-treated rats with 0- and 2-d washout, suggesting that autoreceptor-mediated inhibition was most prominent when NE levels were highest. This provides further evidence that autoreceptor-mediated inhibition of NE neurotransmission remains functional after chronic DMI treatment, arguing against the hypothesis that desensitization of α2-autoreceptors accounts for the delayed onset of action of selective NE reuptake inhibitors.

We studied the relationship of blood and brain levels of imipramine (IMI) and/or its active metabolite desipramine (DMI) to behavioural response, in the tail suspension test (TST). Compared to the control group, doses of 3.75, 7.5, 15, 30 and 60 mg/kg of IMI given intraperitoneally reduced immobility scores significantly. There were significant negative correlations between doses, brain levels of IMI, DMI, IMI + DMI, blood levels of IMI, DMI, IMI + DMI and the animal behaviour. Higher level of IMI and its metabolite in brain and in blood did not impair anti-immobility effect. These findings agree with most results found in men treated with IMI, and suggest a linear or sigmoid relationship between the antidepressant concentrations and its biological response.

Part I of this paper presents a comprehensive review of plasma level monitoring of tricyclic antidepressants (TCAs) and their relationship to clinical response to antidepressant therapy. Imipramine, nortriptyline, amitriptyline, clomipramine and desipramine are the most widely studied TCAs in this regard. Typical therapeutic plasma concentration ranges are suggested for some of these agents, although a consensus is lacking.